An Acidity-Unlocked Magnetic Nanoplatform Enables Self-Boosting ROS Generation through Upregulation of Lactate for Imaging-Guided Highly Specific Chemodynamic Therapy

Chemodynamic therapy is an emerging tumor therapeutic strategy. However, the anticancer effects are greatly limited by the strong acidity requirements for effective Fenton-like reaction, and the inevitably off-target toxicity. Herein, we develop an acidity-unlocked nanoplatform (FePt@FeOx@TAM-PEG) that can accurately perform the high-efficient and tumor-specific catalysis for anticancer treatment, through dual pathway of cyclic amplification strategy. Notably, the pH-responsive peculiarity of tamoxifen (TAM) drug allows for the catalytic activity of FePt@FeOx to be turn-on in acidic tumor microenvironments, while keeping silence in neutral condition. Importantly, the released TAM within cancer cells is able to inhibit mitochondrial complex I, leading to the upregulated lactate content and thereby the accumulated intracellular H+, which can overcome the intrinsically insufficient acidity of tumor. Through the positive feedback loop, large amount of active FePt@FeOx nanocatalyzers are released and able to access to the endogenous H2O2, exerting the improved Fenton-like reaction within the more acidic condition. Finally, such smart nanoplatform enables self-boosting generation of reactive oxygen species (ROS) and induces strong intracellular oxidative stress, leading to the substantial anticancer outcomes in vivo, which may provide a new insight for tumor-specific cascade catalytic therapy and reducing the off-target toxicity to surrounding normal tissues.

Automated summary

A novel nanoplatform was developed in this study, which can achieve high-efficient tumor-specific catalytic anticancer treatment in acidic tumor microenvironments through a cyclic amplification strategy, leading to enhanced Fenton-like reaction. Ultimately, this smart nanoplatform enables self-boosting generation of reactive oxygen species (ROS), inducing strong intracellular oxidative stress, and resulting in substantial anticancer outcomes in vivo.